JC virus, a human polyomavirus, is the viral agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML), and is the cause of death in approximately 5% of AIDS patients. Our efforts in this project have been directed at characterizing the natural variation in the virus that occurs in both the regulatory region and the coding region of the viral genome. The regulatory region of the urinary virus is relatively stable, but appears to rearrange by unknown mechanisms before its attack on the brain of immunocompromised individuals. These brain adapted variants are each unique, and fortunately, appear not to be transmissible from the urine. The concern is that with more PML in the population, brain adapted virus might begin to circulate in those rare instances in which a brain adapted virus also has a selective advantage in the kidney (and in the unknown site of primary infection). To better understand this process, we are examining urine, lymphocytes, and CSF from AIDS patients with and without PML to elucidate the chain of events as the virus adapts to the brain. Other work is covered in the references published within the past year that follow. The work on JC virus has been instructive in understanding the peculiar virulence of some strains of another human polyomavirus, BK virus, in the kidney. Work in collaboration with R. Smith and colleagues in Cincinnati has shown that BK virus associated with end-stage renal disease is rearranged in the regulatory region, and can have coding region mutations as well. Rarely, BK virus can invade the brain in immunocompromised patients with kidney failure, and we plan to follow up such individuals to characterize the changes occurring in the virus. Our work on variations in the coding region of JC virus has also been reported in projects Z01 NS 02929-02 and Z01 NS 02970-01.